key: cord-311453-l6quzef6
authors: Klopfenstein, Timothée; Zayet, Souheil; Lohse, Anne; Selles, Phillippe; Zahra, Hajer; Kadiane-Oussou, N’dri Juliette; Toko, Lynda; Royer, Pierre-Yves; Balblanc, Jean-Charles; Gendrin, Vincent; Conrozier, Thierry
title: Impact of Tocilizumab on mortality and/or invasive mechanical ventilation requirement in a cohort of 206 COVID-19 patients
date: 2020-08-13
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.08.024
sha: 
doc_id: 311453
cord_uid: l6quzef6

INTRODUCTION: No therapy has proven to be effective yet to reduce mortality and/or invasive mechanical ventilation (IMV) requirement in COVID-19. Tocilizumab (TCZ) in patients with severe COVID-19 could be an effective treatment. METHOD: We conducted a retrospective case-control study in the Nord Franche-Comté Hospital, France. We compared the outcome of patients treated with TCZ and patients without TCZ considering a combined primary endpoint: mortality and/or IMV requirement. RESULTS: Thirty patients were treated with TCZ and 176 patients were treated without TCZ. TCZ was used in patients in a critical condition (oxygen therapy flow at TCZ onset was 10.5 l/min and 14/30 patients had ≥ 50% lung involvement on CT scan) as a rescue treatment (8/30 patients who died were not admitted in USC in regards to their comorbidities). However, mortality and/or IMV requirement were lower in patients with TCZ than in patients without TCZ (27% vs 52%, p = 0.009). CONCLUSION: Despite the small sample size in the group TCZ, this result suggests that TCZ reduces mortality and/or IMV requirement in patients with severe SARS-CoV-2 pneumonia. This notion needs to be confirmed and spread in the medical community.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now been threatening human health for months. Intensive care unit (ICU) capacities are challenged to face this outbreak (1) . Data is particularly needed on treatments able to reduce mortality and the number of critical ill patients (2) . Death mainly results from acute respiratory distress syndrome (ARDS) (3) .

Markers of inflammation such as C-reactive-protein (CRP), ferritin, and interleukin-6 are significantly associated with mortality (4, 5) . Coronavirus disease 2019 (COVID-19)-related multiple-organ failure and ARDS are mainly caused by cytokine storm (6) . Post-viral hyper-inflammation, which begins in the second week of the disease, seems to explain disease severity (7) . Tocilizumab (TCZ) is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. Several arguments show that TCZ administered to patients with severe COVID-19 could be an effective treatment to reduce mortality. By neutralizing a key inflammatory factor in the cytokine release syndrome (CRS), this molecule may block the cytokine storm during the systemic hyperinflammation stage and reduce disease severity (8, 9) . Studies comparing the outcomes of patients treated with and without TCZ are scarce, and include small numbers of patients (10) . We have recently published a retrospective study including 45 patients treated in our hospital, which shows that TCZ seems to reduce the number of COVID-19 severe cases and/or mortality (11) . In this work, we aim to extend this study to our entire J o u r n a l P r e -p r o o f patient population with confirmed COVID-19 to compare the outcome, especially in terms of need for invasive mechanical ventilation (IMV) and/or mortality, between patients treated with TCZ and without TCZ.

We have conducted a retrospective case-control study in NFC (Nord Franche-Comté) Hospital. On March 1 st , a first case of COVID-19 was confirmed in our hospital. "Standard treatment" was administered to patients requiring oxygen therapy: hydroxychloroquine or lopinavir-ritonavir therapy or corticosteroids and antibiotics. On April 1 st , in relation with the increasing medical literature data, the NFC hospital scientific medical committee including infectious diseases specialists, ICU specialists, rheumatologists, biologists, and pharmacists, approved the off-label use of TCZ in patients with general status deterioration despite well-conducted standard care. Daily "tocilizumab multidisciplinary team meetings" were organized to discuss patients' eligibility to receive TCZ. Based on the medical literature, we checked several criteria before starting TCZ treatment: no contraindication to TCZ, confirmed COVID-19 with real-time reverse transcription (RT)-PCR SARS-CoV-2 RNA, failure of standard treatment, period since symptoms onset ≥ 5 days, oxygen therapy ≥ 4 liters/min, ≥ 25% of lung damages on chest computed tomography (CT) scan, and ≥ 2 parameters of inflammation or biological markers of mortality (with a high level) such as ferritin, CRP, D-dimer, lymphopenia, and/or lactate dehydrogenase.

The present work compares two groups of patients.

The "tocilizumab group" (TCZ group) included all patients (except patients already in intensive care unit with IMV) whom received standard treatment and TCZ (8mg/kg per dose, 1 or 2 doses). Between April 1 st and May 11 th , 2020, we enrolled all adult patients who received TCZ for confirmed COVID-19 by RT-PCR SARS-CoV-2 RNA. All patients receiving TCZ were informed that this prescription was used outside of its marketing authorization indications; they were also informed that they could deny the administration of TCZ. In practice, several patients received TCZ when there were in critical condition J o u r n a l P r e -p r o o f as a rescue treatment; in order to judge the effectiveness of TCZ administration we excluded patients who had received the first dose of TCZ less than 24h before intubation and/or death.

The standard treatment group (ST group) included patients receiving standard treatment but without TCZ. On average, patients received TCZ seven days after admission in our hospital (11) , so we stopped the inclusion in the ST group one week before TCZ availability. We excluded patients who hadn't received the standard treatment. This group included all hospitalized adult patients with confirmed COVID-19 RT-PCR SARS-CoV-2 RNA between March 1 st and March 24 th , 2020. Because patients from the TCZ group were all critically ill patients, and for comparative purposes between the two groups, we excluded from the control group the patients with moderate disease (i.e. those hospitalized for less than 48 hours and/or patients without any COVID-19 symptoms) and patients who were less than 50-year-old (as none of the patients in the TCZ group was younger than 50 yearsold).

In all patients, diagnosis of COVID-19 was confirmed by RT-PCR on respiratory samples. Briefly, viral RNA was extracted using the NucleoSpin®RNA Virus kit (Macherey-Nagel) according to the manufacturer's instructions, and amplified by RT-PCR protocols developed by the Charité (E gene) (12) and the Institut Pasteur (RdRp gene) (13) on LightCycler 480® (Roche).

We collected the following data from the medical files of patients in both groups: demographic characteristics, comorbidities and outcome. To increase statistical power, we chose a combined primary endpoint (mortality and/or IMV requirement) to compare the two groups. Continuous variables were expressed as mean and standard deviation (SD) and compared with ANOVA test.

Categorical variables were expressed as number (%) and compared by χ 2 test or Fisher's exact test between the two groups. A P-value < 0.05 was considered significant. We used the SPSS v24.0 software (IBM, Armonk, NY, USA).

We have included 30 patients in the TCZ group. Thirty-three patients with confirmed COVID-19 were treated with TCZ before intubation between March 1 st and May 11 th , 2020. Three patients intubated less than 24 hours after TCZ first administration were excluded. We included 176 patients out of 661 patients who were assessed for eligibility in the ST group ( Figure A) .

Concerning the TCZ group, oxygen therapy flow at TCZ onset was 10.5 l/min [1.5-15] , the time of first symptoms and of admission to TCZ onset was respectively 11.7 days [5-21] and 6.5 days .

Patients had high serum levels of C reactive protein (CRP) (mean 142 mg/l) and ferritin (mean 1496 ng/ml) at TCZ onset. Forty-seven percent of patients (14/30) had ≥ 50% lung involvement on CT scan.

Concerning TCZ administration, 27 patients had 2 doses of TCZ (second dose given 24 to 72 hours after the first dose) and only 3 patients received a single dose.

No statistical differences were observed between the two groups (TCZ and ST) with regard to age, sex, and comorbidities (Table 1) .

Our combined primary endpoint (mortality and/or IMV requirement) was higher in the ST group than in the TCZ group (52% vs 27%, p= 0.009) ( Figure B ). Patients in the ST group clearly required IMV more often than patients in the TCZ group (22% vs 0, p=0.004); however, no statistical difference was observed between the two groups in terms of mortality. The 8 patients who died in the TCZ group were not admitted in USC in regards to their comorbidities.

It's interesting to notice that none of the three patients intubated less than 24 hours after TCZ first administration died (two were discharged and one was still hospitalized). Furthermore, if we included these 3 patients, mortality and/or IMV requirement was still higher in the ST group than in the TCZ group (92/176 [52%] vs 11/33 [33%], p= 0.046).

Despite the small sample size of the TCZ group, the latter strongly suggests that TCZ may reduce the number of mortality and/or IMV in patients with severe SARS-CoV-2 pneumonia.

Our population is older, with more comorbidities, and a higher level of mortality than other studies with COVID-19 patients (5, 14) . These results are probably explained by the exclusion of patients without hospitalization criteria and less than 50 years old (in order to have a comparable population with the TCZ group).

Patients in TCZ group seemed to be more severe than patients in ST group. In TCZ group, patients had a higher respiratory rate and a lower PaO2/FiO2 ratio at admission than ST group but without statistical differences. Biological findings at admission were worse in TCZ group than ST group especially for ferritin, D-dimer and Lactate dehydrogenase which are known on high level as predictive of poor outcome. Furthermore, during hospitalization patients with TCZ required a higher level of oxygen therapy (L/min) than patients with ST (11.8 vs 8.1, p <0.001).

The two groups differ about standard treatment. Lopinavir/ritonavir was only administered in "Standard Treatment" group. On the contrary, hydroxychloroquine and corticosteroids were more often administered in TCZ group. This is explained by the local management during the crisis, in our hospital lopinavir/ritonavir was recommended in the beginning of the outbreak and after a few weeks was replaced by hydroxychloroquine. Then, in the end of the first period of inclusion, corticosteroids were an alternative treatment.

TCZ was administered on average 12 days after COVID-19 symptoms onset, after standard treatment failure. It was prescribed on average 6.5 days after admission, after standard treatment failure in most cases, in patients presenting comorbidities in 83% of cases and who were critically ill (mean oxygen flow of 10.5 L/min). However, compared with the ST group, the occurrence of mortality and/or IMV requirement was clearly lower (27% vs 52%, p= 0.009).

None of our 30 TCZ-treated patients needed IMV. Finding enough ICU beds is highly challenging during the present COVID-19 pandemic (1); TCZ could be the key in the treatment of COVID-19 cases to reduce ICU admissions. It could also have a huge public health impact as well as an impact on reducing the human and economic cost of the outbreak.

Only few Case reports and series have reported that repeated doses of TCZ may improve the condition of critical patients (8, (15) (16) (17) (18) (19) (20) . Only Capra et al. reported a case-control study which shows that TCZ decreases mortality rate in patients with COVID-19 related pneumonia (10) . In their study, two out of 62 patients of the TCZ group and 11 out of 23 in the control group died, patients receiving TCZ showed significantly greater survival rate as compared to control patients with a hazard ratio for death at 0.035 (95% confidence interval, 0.004 to 0.347; p = 0.004), adjusting for baseline clinical characteristics. In a recent observational, controlled study of 154 patients with severe COVID-19 illness requiring mechanical ventilation, tocilizumab was associated with a 45% reduction in the hazard of death (19). The same kind of results were found by Rossotti et al. in a comparative analysis between seventy-four patients treated with TCZ and 148 patients controls (20). The low number of patients included in our work in the TCZ group may explain that the difference in mortality is not significant because of a lack of statistical power. However, the main reason is probably that we administered TCZ in many cases as a rescue treatment in critical patients who were too old and comorbid to be transferred in ICU. Therefore, the 8 patients who received TCZ and died were not admitted in ICU due to their comorbidities. Furthermore, we have already published that our patients who received TCZ were older, presented more comorbidities and were more critically ill than a control group selected with the same methodology but in a shorter period of time (11) .

The post-viral hyperinflammation onset on the second week of the disease seems to explain COVID-19 disease severity. By neutralizing a key inflammatory factor in the cytokine release syndrome TCZ may block the cytokine storm during the systemic hyperinflammation stage and reduce disease severity. We don't have data about the right timing for TCZ administration, in our study TCZ was administered on average 12 days after onset of symptoms. However, TCZ should probably be administrated earlier in the second week of the disease.

Our study is retrospective with a low number of patients in TCZ group. Larger prospective randomized trials are required to confirm these findings.

Our results suggest that tocilizumab reduces mortality and/or invasive mechanical ventilation requirement in patients with severe SARS-CoV-2 pneumonia. This notion needs to be confirmed and spread in the medical community. 

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Conflict of interest. The authors declare that they have no conflict of interests. J o u r n a l P r e -p r o o f

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The authors thank especially Emmanuel Siess, Azzedine Rahmani, Charlotte Bourgoin, Elodie Bouvier, Julien Lorenne and Frederic Deuze for their strong implication in the present work.They also thank the management team of the Hospital Nord Franche-Comté for having made available Tocilizumab outside its approved indication and each member of the HNF Hospital Tocilizumab multidisciplinary team.Special acknowledgements to all the physicians, caregivers (nurses and orderlies) and patients.
